The functional Magnetic Resonance Imaging (fMRI) group of the Clinical Brain Disorders Branch consists of multidisciplinary specialists with expertise in neurology, psychiatry, physics, biology, and MRI techniques. This group pursues a variety of research agendas involving study of brain function and metabolism in normal healthy controls and patients with neuropsychiatric disorders. Over the last year the group has continued to make more strides in the field of ?Imaging Genomics?, a paradigm in brain research using clinical genetics and neuroimaging, to explore the basic molecular biology and genetics of human information processing in normal health and as related to major psychiatric illnesses. Interesting findings have emerged from these studies: 1) In a study aimed at exploring the effects a genetic variation in the brain-derived necrotrophic factor (BDNF) gene on hippocampal gray matter volume we found bilateral reductions of hippocampal gray matter volumes in methionine carriers (met-BDNF) compared with valine carriers (val/val-BDNF) subjects. The met-BDNF carriers also exhibited additional reduced gray matter volumes predominately in the lateral portion of the frontal lobes. These findings are consistent with the cellular and clinical effects of the BDNF valine to methionine polymorphism and suggest that this change of an amino acid also affects the anatomy of the hippocampus and prefrontal cortex (PFC), identifying a genetic mechanism of variation in brain form and structure related to learning and memory. 2) In another study, exploring the effects of a functional polymorphism in a regulatory region of the human serotonin transporter gene (SLC6A4), we found that s-carriers (serotonin short protein-carriers), had significantly reduced bilateral gray matter volumes in both the amygdala and the subgenual anterior cingulate. We also found that the serotonin s-allele effect on subgenual cingulate volume is dramatically reduced in met-BDNF allele carriers in comparison to val/val-BDNF carriers. Together, these results suggest that the valine to methionine BDNF polymorphism may be a modifying genetic factor for depression, because it affects development and plasticity of critical brain systems involving serotonin related to the experience of negative mood and may lead, together with abnormal serotonin function (s-allele), to an anatomical substrate reflecting an increased vulnerability for depression. The group also performed studies in patients with schizophrenia to explore the integrity of brain structures underlying cognitive function and affective behavior. In one study aimed at exploring the phenomenon of low activity and hyperactivity of the dorsolateral prefrontal cortex in schizophrenia, the groups were subdivided on the basis of performance on the working memory task into high or low performing subgroups. Results show that in high-performing schizophrenic patients there were locales of greater prefrontal cortex activation as well as locales of less activation. While only locales of low prefrontal cortex activation were found in the low performing schizophrenic patients. These findings suggest that patients with schizophrenia whose performance on the N-back working memory task is similar to that of healthy comparison subjects, but they use greater prefrontal cortex resources and achieve lower accuracy (i.e., inefficiency). Other patients with schizophrenia fail to sustain the prefrontal cortex network that processes the information, achieving even lower accuracy as a result. These findings add to other evidence that abnormalities of prefrontal cortical function in schizophrenia are not reducible to simply too much or too little activity but, rather, reflect a compromised neural strategy for handling information mediated by the dorsolateral prefrontal cortex. The group has also been exploring the effects of neuropharmacological manipulation on brain information pproocessing. Based on recent evidence which suggests that catechol-O-methyl transferase (COMT) may play a unique role in regulating dopamine (DA) flux in the PFC, the group has explored if Tolcapone (TOL), a COMT inhibitor which penetrates the blood brain barrier can improve efficiency in PFC function. Preliminary results from this study suggest that TOL does enhance the efficiency of prefrontal cortical information processing, and add to evidence that COMT plays a significant role in modulating DA tone in the PFC. The impact of COMT genotype on these effects is also being explored. 2) In another study, using event-related fMRI, we examined at the effects of oral dextroamphetamine treatment on brain activity and during active mental processing. We found that presumably by enhancing tonic over phasic activation, dextroamphetamine treatment ?equalized? levels of ventral striatal activity and positive arousal during anticipation of both gain and loss. These findings suggest that therapeutic effects of dextroamphetamine on incentive processing may involve reducing the difference between anticipation of gains and losses. The group also pursued studies to explore the neurophysiological correlates of altered brain function associated with senescence. In a study aimed at exploring the neurophysiological correlates of reduced working memory capacity with age we found that within working memory capacity (as in 1-Back) when the elderly performed as well as the younger subjects, they showed greater prefrontal cortical (BA 9) activity bilaterally. At higher working memory loads (as in 2-Back and 3-Back), however, when they performed worse then the younger subjects, the elderly showed relatively reduced activity in these prefrontal regions. These data suggest that within capacity, compensatory mechanisms such as additional prefrontal cortical activity are called upon to maintain proficiency in task performance. As cognitive demand increases, however, they are pushed beyond a threshold beyond which any compensation can be made probably from a failure to engage such compensatory mechanisms. This leads to a decline in performance. Studies are being pursued to explore the effect of aging on other brain systems, and the role of genetics on these changes.